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Synthetic chimeric peptidesSynthetic chimeric peptides description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20090162369, Synthetic chimeric peptides. Brief Patent Description - Full Patent Description - Patent Application Claims
This application claims priority benefit of U.S. provisional application Ser. No. 61/007,570, filed Dec. 12, 2007, which application is incorporated herein by reference in it entirety. The present invention relates generally to chimeric peptides comprising one or more protective epitopes in a conformation enabling immunological interactivity and to vaccine compositions comprising the same. The present invention is particularly directed to a chimeric peptide capable of inducing protective antibodies against Group A streptococci (GAS). A List of References of the publications referred to in this specification by author are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the amino acid sequences referred to in the specification are defined following the bibliography. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. The coiled coil structure is an important structural and biologically abundant motif found in a diverse group of proteins (Cohen and Parry, 1990, 1986) and many proteins which may be useful vaccine candidates against various diseases have been found to possess a coiled coil structure. More than 200 proteins have now been predicted to contain coiled coil domains (Lupas et al., 1991). These include surface proteins of certain bacteria such as streptococcal protein A and M proteins; viruses such as influenza hemagglutinin and human immunodeficiency virus (HIV) glycoprotein gp45; and protozoa such as VSG of Trypanosomes. All coiled coil motifs share a characteristic seven amino acid residue repeat (a-b-c-d-e-f-g)n. The X-ray structure of several coiled coil domains have been solved and these include the leucine zipper portion of the yeast transcription factor GCN4 dimer (O\'Shea et al. 1991), the repeat motif of 1-spectrin (Yan, 1993), together with the GCN4 leucine zipper trimer (Harbury et al., 1994) and tetramer (Harbury et al., 1993) mutants. In the development of a subunit vaccine based on these proteins, it is generally difficult to map epitopes within the coiled coil structure. Furthermore, protective epitopes may need to be presented in the correct conformation for immunological recognition, such as antibody binding. This is especially important in defining a stable minimal epitope and using it as a vaccine. Streptococcus pyogenes, also known as Group A Streptococcus (GAS), is a serious human pathogen capable of causing a variety of human diseases ranging from uncomplicated pharyngitis and pyoderma to severe life threatening invasive infections. Infections caused by GAS range from uncomplicated skin and soft tissue infections to life threatening invasive diseases such as bacteremia and necrotizing fasciitis as well as non-supperative sequalae such as rheumatic fever, rheumatic heart disease and acute glomerulonephritis. Infections due to GAS represent a public health problem of major proportions in both developing and developed countries. Illness attributable to GAS infection results in a huge burden to health care systems worldwide, as there are an estimated over 25-35 million infections per year in the US alone. Although uncomplicated pharyngitis and skin and soft-tissue infections account for most of these infections, there is a resurgence in the incidence of the life-threatening illnesses, such as necrotizing fasciitis and toxic shock syndrome, in hospitals and other institutions. Uncomplicated infection can also lead to serious sequelae, such as, acute rheumatic fever (ARF) and glomerulonephritis. Acute rheumatic fever continues to be a leading cause of heart disease worldwide. WHO estimates that GAS causes 517,000 deaths worldwide annually, with approximately one-third of those deaths (163,000) related to invasive GAS disease and the remainder (354,000) related to nonsuppurative sequelae of GAS infections (Bisno et al., 2005). Presently, penicillin is still used as a first-line therapy in the treatment of most GAS infections. Currently available methods of prevention are either inadequate or ineffective, as evidenced by the morbidity and mortality still associated with this pathogen worldwide. The current situation with respect to the health care burden and the treatment and prevention of GAS infections therefore warrants the development of other preventative/therapeutic treatment measures. The surface M protein is the major virulence determinant and protective antigen of GAS. In the immune host, M protein antibodies are opsonic and promote ingestion and killing of GAS by phagocytic cells. The M proteins of GAS isolates are multivalent and may elicit the production of antibodies that cross-react with human tissues. M protein contain a seven-residue periodicity which strongly suggested that the central rod region of the molecule is in a coiled coil conformation (Manula and Fischetti, 1980). Overlapping peptides were made that spanned this region (see WO 93/21220) and mouse antibodies raised against one synthetic 20mer peptide (designated “p145”) from the highly conserved C-terminal region can opsonise and kill multiple isolates of GAS (Pruksakorn et al., 1994a). In addition, p145 can inhibit in vitro killing mediated by human sera. Of concern is that p145 may also stimulate heart cross-reactive T cells (Pruksakorn et al., 1992; 1994b). The B cell epitope within p145 was thought to be conformational because truncated peptides fail to elicit a protective antibody response (Pruksakorn, 1994). Non-host reactive, conformationally constrained, minimal B cell epitopes of the GAS M protein have now been identified (WO 96/11944; Heyman et al. 1997). WO 96/11944 describes chimeric peptides in which a first amino acid sequence comprising a conformational epitope is embedded within a second amino acid sequence, wherein the first and second amino acid sequences are derived from peptides, polypeptides or proteins having similar native conformations. The second amino acid sequence provides a “framework” for the first amino acid sequence. WO96/11944 discloses mapping the conformational epitope within the p145 peptide from the conserved C-terminal region of the GAS M protein (e.g. Example 14). Chimeric peptides were constructed in which a 12 amino acid window of p145 sequence was inserted into the leucine zipper motif in GCN4, the DNA binding protein of yeast (O\'Shea et al., 1991). The 12 amino acid window of peptide 145 sequence was inserted into the so-called “Jcon” peptide derived from leucine zipper motif in GCN4 in such a way as to preserve any potential helical structure. The window was shifted one residue at a time to give nine peptides (referred to as J1→J9) that represented the entire p145 sequence. There is still a need for improved vaccines, for example, against GAS associated diseases. In addition, poor vaccination uptake, the on-going health risk for non-immunized individuals infected with GAS, and the possible ill-health in immunized individuals in the early phase of a sever acute GAS infection e.g., before an immune response is mounted, make other therapeutic and prophylactic approaches for the treatment of GAS infection desirable. Such therapies may be adjunct to other treatments such as vaccination or antibiotics, or stand-alone therapies. The present inventors have now found that chimeric structures based on the p145 amino acid sequence inserted with a framework structure comprising a second amino acid sequence provide unexpectedly improved immunogenicity. Furthermore, the chimeric peptides have also been found to be protective against multiple strains of the same streptococcal Grouping, e.g. Group A streptococci. In addition, it is contemplated that the chimeric peptides of the present invention will be useful against multiple Groups of streptococci, i.e. in addition to the Group A, also, for example, Group C and/or Group G. Accordingly, the present invention provides a chimeric peptide comprising a first amino acid sequence comprising a conformational epitope inserted within a second amino acid sequence wherein the first and second amino acid sequences are derived from peptides, polypeptides or proteins having similar native conformations, wherein the first amino acid sequence has at least three amino acids selected from within the following sequence:
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